The Alzheimer’s disease community has grown accustomed to news of an endless string of failures in clinical trials of potential treatments. In fact, only four such treatments went on to win approval between 1998 and 2014 — addressing symptoms but not altering the relentless course of the disease.

PhRMA — a group of major U.S. pharmaceutical companies — recently released a list of treatments currently in clinical development for Alzheimer’s, along with a “Medicines in Development 2017 Update” to reassure patients and caregivers that all these failed trials have advanced disease understanding, and that this is reflected in new efforts.

But what does this list of more than 80 drugs in testing tell us? Do these trials hold a promise to deliver where others have not? And what exactly have scientists learned from the 123 treatments that failed in clinical studies since 1998?

“We absolutely are working with the highest sense of urgency to try to bring effective therapies to patients. But it is a long road of learning,” said Dr. Matthew Kennedy, director of Early Discovery, Neuroscience, at Merck and a PhRMA representative. “I’m very excited about what the next few years might bring.”

Dr. Dean Hartley, director of scientific initiatives at the Alzheimer’s Association, agrees that a breakthrough may be among current treatments in development. He too underscored that, while it may not be apparent, the research field is moving forward, with key information available that was lacking only a few years ago.

Learning from failure

For anyone not directly involved in Alzheimer’s research, this new knowledge may be hard to spot, particularly since drugs targeting amyloid-beta — making up a large proportion of earlier trial failures — are still a main focus of studies.

But as scientists, both Kennedy and Hartley are confident that lessons have been learned, especially where patient groups in trials are concerned. Knowledge has leapt regarding which patients are the likely best candidates for potential treatments, and what disease states might benefit most.

Dr. Dean Hartley

One reason for this: Large brain imaging studies have revealed that some 30 percent of people diagnosed with Alzheimer’s do not have amyloid in their brains, Hartley said.

Methods allowing researchers to image two Alzheimer’s-associated proteins — amyloid-beta and tau — in living people have only been around for a short time, and older studies had no way of knowing if a person had these proteins in significant aggregation, or even the disease itself — at least, not until a post-mortem examination.

“I think the key difference, and what I’m very excited about … is that we’re getting much, much better at defining the right patient population,” Kennedy said. “We’re going to be able to go into earlier stage patients with a much higher degree of confidence of where their pathology is.”

And, Kennedy underscored, data consistently demonstrate that current medications need to be given earlier, before patients lose too many brain cells.

Even people with mild or moderate Alzheimer’s have already suffered substantial neurodegeneration, he said of this data. So trials now attempt to recruit patients with so-called prodromal Alzheimer’s disease — people whose memory issues are so minor they pass unnoticed except to closest family and friends.

Research also shows that disease processes start up to two decades before symptoms begin showing. That’s another reason identifying patients early in this process is now a key research focus.

The many trial failures led some experts to dismiss amyloid as a cause of Alzheimer’s. But both Kennedy and Hartley are certain of amyloid’s importance, either as a disease cause or result. Still, they agree the failed trials did not show that treatments really affected amyloid aggregation.

“If anything, the evidence is that they have not,” Kennedy said, explaining that for many investigated compounds — particularly antibodies — it has been difficult to assess if the drug really gets into the brain and does what it is supposed to do.

This may be about to change.

A world of biomarkers

Biomarkers are measurements that may tell us something about a biological process — sugar levels in the blood, for instance, in diabetes. But with the brain of a living Alzheimer’s patient largely inaccessible, alternative ways of taking such measures are essential.

Brain imaging that allows researchers to see how much amyloid plaques are present in a person’s brain is now standard in trials. Tools like PET scans assist both in bringing ideal patients to a trial, and in demonstrating if a drug is having an impact on telltale disease signs.

Dr. Matthew Kennedy

A result, Kennedy pointed out, is that some investigative treatments appear to be showing effects. Biogen’s anti-amyloid beta antibody aducanumab, for example, aggressively reduces the amount of brain amyloid, he said. Ongoing research will determine if that reduction translates to slower disease progression.

“And the next phase of introducing imaging agents will be to have everyone scanned for the presence of tau pathology,” Kennedy said. Researchers believe that tau, making up neurofibrillary tangles that build inside neurons in Alzheimer’s patients, might also contribute to disease processes. And studies suggest the presence of amyloid aggregates drive tau accumulation.

Imaging is only one of the emerging tools helping scientists better understand the disease and possible treatments. Measures of molecules in the spinal fluid and blood are also more commonly used, as are markers of neuroinflammation — a feature that researchers increasingly believe play an important role in Alzheimer’s development.

A long list of compounds

So what can patients expect from the 80-plus compounds on the PhRMA list? Some there have already failed, like Eli Lilly‘s solanezumab late last year, and, more recently, Axovant‘s intepirdine. Will this trend continue?

Possibly not, as now there are treatments with a documented impact on amyloid beta accumulation, such as aducanumab. Compounds that target BACE1, an enzyme directly involved in producing amyloid, may also make a difference.

Merck’s own BACE1 blocker, verubecestat — which Kennedy himself worked to develop for about 18 years — has been seen to lower brain amyloid in early studies. It is being tested in prodromal Alzheimer’s patients in the ongoing Phase 3 APECS trial (NCT01953601).

Asked to name the efforts he finds most promising, Hartley said that immunotherapies — mainly, antibodies lowering amyloid or tau — are particularly alluring since they cause few side effects.

The hope is that by immunizing people early in life, they may never develop Alzheimer’s, Hartley said. “I think the immunotherapy area is probably going to show some of the earliest effects in changing the course of the disease,” he said.

Treatments that target neuroinflammation in Alzheimer’s may also have an impact. And armed with the new imaging tools like PET, researchers can now begin to understand how amyloid, tau and brain inflammation interact to cause the disease.

Combining approaches

With all the talk of complexity, it may be surprising that Alzheimer’s trials only test single compounds. Might combination approaches, used widely in cancer treatment, succeed where single agents have failed?

Kennedy agreed, but underscored that to combine therapies, researchers first need a good understanding of how the drug acts and how safe it is on its own. For the first time, several compounds are in development that now have such data, he said.

“I am hopeful that they will be sort of a cornerstone mechanism that can be combined with the tau agents, since it’s been shown that they have good tolerability for chronic treatment and very robust effects on suppressing amyloid-beta production,” Kennedy said. He added that with the new focus on tau and inflammation, along with approaches targeting metabolism and neuron function, researchers have more options to combine.

Widening a narrow focus

Kennedy and Hartley, speaking separately, clearly shared many views regarding Alzheimer’s treatments in development. When asked if scientists had focused too much on amyloid beta, both agreed.

“We certainly need to take a broad look at this disease because the disease is quite diverse in the changes that are happening in the brains of AD patients,” Kennedy said. Still, he and Hartley argued that there were good scientific reasons for focusing on amyloid in the first place.

Hartley also underscored that a long-term lack of funding limits the focus. Alzheimer’s research has, for decades, received only a fraction of the public and private money awarded to cancer and heart disease research.

“Were other things [in Alzheimer’s trials] ignored? Probably yes,” said Hartley, who nonetheless is optimistic that recent increases in funding, coupled with lessons learned from failures, will make a difference.

Both also speak of the importance of better studies into lifestyle prevention measures, emphasizing how studies for heart disease advanced treatment and prevention.

“What do you do throughout your life, what do you eat, how do you exercise, what are your cholesterol levels?” asked Hartley, speaking of how researchers came to understand heart disease by following patients in large trials that asked these questions.

“How do we also think about brain health in that way?” Kennedy asked. While observational studies have allowed researchers to glean plenty of risk factors for Alzheimer’s — including heart disease — no large prospective trials have tackled prevention.

They both also think that one big breakthrough will create a snowball effect in developing treatments. For this reason, researchers across pharmaceutical companies and academic institutions work together, aided by organizations such as the Alzheimer’s Association, culturing the belief that such a breakthrough may be just around the corner, they said. (A related article on collaborative efforts in Alzheimer’s can be read here.)

“I’m very excited about what the next few years might bring,” said Kennedy. “I think we’re going to learn an enormous amount.”

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6 comments

OK. This is all very nice and optimistic and sounds like everything is being done. However, what about the elephant in the room that no one wants to discuss? I’m talking about off-label prescription of already approved drugs which research has shown to have potential for repurposing for Alzheimer’s. From my experience, nobody seems to want to touch that route–neither individual physicians nor institutions. Why? The most obvious conclusion is that there is no money to be made from using out-of-patent or generic drugs. So, no sponsorship of research, etc. It is estimated that 20% of all drug prescriptions to patients generally are made on an off-label basis–except for Alzheimer’s. This is unconscionable and must be changed. As an Alzheimer’s caregiver, I am tired of watching my wife fade away while big Pharma exploits my grief for its monetary gain. Where are the voices of reason and compassion in this tragedy?

Why is intranasal insulin not mentioned? Insulin resistance, hypometabolism of glucose in the brain has been repeatedly mentioned by top-notch research groups in the field in the past as well as most recent publications in 2017 as the cause and an avenue of therapy for AD – especially in view of the failures of amyloid/tau focused approaches. There are ongoing clinical studies on AD, post-stroke cognition impairment, HAND – HIV-associated Neurocognitive Disorder….

The real breakthrough is we have reached a tipping point in Alzheimer’s research. We now know a causal factor of Alzheimer’s is Aluminum accumulation in the brain. We also know dissolved silica facilitates the elimination of Aluminum and stabilizes or improves the cognition of those with Alzheimer’s. Look at Dennis N Crouse’s book Prevent Alzheimer’s, Aluminum and Stroke with 7 Supplements, 7 Lifestyle choices and a Dissolved Mineral. Chapter 1 is available on his website.

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